The present invention relates to the field of supplemental products, and more particularly, but not exclusively, to novel magnesium (Mg)-containing products, method of preparing same and uses thereof as magnesium supplements with enhanced bioavailability in humans.
Magnesium is a natural element widely diffused in living organisms, especially in mammals, wherein the largest concentration thereof occurs in bones. The participation of magnesium ions in the human body has been established in most reactions of carbohydrates, lipids, nucleic acids, and in protein metabolism.
Magnesium is the fourth most abundant cation in the human body and plays an essential physiological role in many of its functions. This role is achieved through two important properties of magnesium; the ability to form chelates with important intracellular anionic-ligands, especially ATP, and its ability to compete with calcium for binding sites on proteins and membranes. By competing with calcium for membrane binding sites and by stimulating calcium sequestration by sarcoplasmic reticulum, magnesium helps to maintain a low resting intracellular free calcium ion concentration which is important in many cellular functions. The electrical properties of membranes and their permeability characteristics are also affected by magnesium.
Magnesium, being a normal component of the blood plasma and a calcium antagonist, takes part in the muscle contraction mechanism and is vital for the action of a number of enzymes. Magnesium balance in organism is tightly controlled by the dynamic action of intestinal absorption, exchange with bone, and renal excretion.
Magnesium is estimated to be distributed in the body as follows: 53% in the bone, 27% in muscle, 19% in soft tissue, 0.5% in erythrocytes, and 0.3% in serum. Of the serum magnesium, 33% is protein-bound, 12% is complexed to anions, and 55% is in the free ionized form. Total magnesium stores in the body average 24 grams (2000 mEq) elemental magnesium, and a normal serum concentration is in the range of 1.7-2.5 mg/dL (1.4-2.1 mEq/L).
Mg is transported to the different body compartments in the blood plasma, either as free ionized Mg, bound to relatively small (ultrafiltrable) complexes (e.g. citrate) or bound to proteins (albumin, globulin), which are not ultrafiltrable. The concentration of Mg in serum is kept relatively constant. However, it has been shown that there is no apparent correlation between serum and tissue magnesium levels, with exception of bone and interstitial fluid, and therefore serum magnesium measurements do not accurately reflect the amount of magnesium present in the body.
Magnesium excretion is the main pathway for regulating Mg levels in the blood. About 70-80% of plasma Mg (ultrafiltrable Mg) is filtered in the kidney. Of this ultrafiltrable Magnesium, 20-25% is reabsorbed by the proximal tube, 50-60% in the loop of Henle, and 5% in terminal segments, while the remainder (5-20%) is excreted in the urine. Magnesium is excreted from the gastrointestinal tract at a rate of approximately 2 mEq/day. Further significant loss of magnesium can be caused by drugs such as amphotericin B, cisplatin, digoxin, pentamidine, gentamicin, and loop diuretics via renal wasting of magnesium in the renal tubule.
The daily magnesium requirement for humans ranges from 5 to 10 mg/per kg body weight, and is normally supplied through the food, particularly vegetables. However, as the magnesium food content in the Western world is consistently reducing, magnesium deficiency, or hypomagnesaemia, has become a prevalent condition. While the average daily intake of magnesium at the beginning of the 20th century was 410 mg, today it is only 200-300 mg. This is attributed to the processed nature of the contemporary diet (Seelig and Rosanoff, 2003).
The current daily Recommended Dietary Allowances for magnesium is 420 mg/day for males and 320 mg/day for females above 31 years, with an additional 300 mg/day during pregnancy or physical growth. Surveys show that a substantial number of adults in the United States fail to consume recommended daily amounts of magnesium. Dietary surveys show that the average intake in many western countries is less than the RDA (Saris et al., 2000). In a population-based study of 30-year old Israelis, about 60% had magnesium deficiency (Shechter, 2010; Seelig, 1964; Centers for Disease Control and Prevention, 1994).
Magnesium homeostasis is essential for many intracellular processes and depends on the balance of intestinal absorption and renal excretion. Hypomagnesaemia may arise from various disorders. A magnesium deficiency, or hypomagnesaemia, is common in hospitalized patients, especially in the elderly with coronary artery disease (CAD) and/or those with chronic heart failure. Hypomagnesemia is often associated with increased incidence of diabetes mellitus, metabolic syndrome, mortality rate from coronary artery disease (CAD) and all cause.
Hypomagnesaemia is also associated to abnormal muscle excitability as well as convulsions, to psychiatric disturbances, and to calcium and/or potassium abnormalities.
Diminished content of magnesium in blood serum contributes to the development of hypercalcemia, spasm of arterioles, and the occurrence of muscular convulsions and trophic disorders and thus plays an essential role in the pathogenesis of changes of the blood flow and trophic disorders.
Magnesium deficiency can occur in babies from birth, when the mother was already depleted of her own magnesium reserves, or when the baby is poorly supplied with magnesium, and/or undergoes high magnesium losses from his or her organism. When encountered in an adolescent, adult or aged person, a magnesium deficiency can be also ascribed to generally stressing conditions, chronic intoxication or disease, to malabsorption, to alcohol or drugs abuse, as well as to hormone pathologies that cause magnesium losses for long time periods. A magnesium deficiency referable to a poor supply can be also due to, e.g., growth, pregnancy, breast feeding, anorexia, vomiting, overload of calcium, of vitamin D, of phosphorus, of alkalizing products, or excessive intake of alimentary fiber, low calorie diets, alcoholism, etc. A magnesium deficiency referable to defects in magnesium metabolism can be due to, e.g., stress or neurosis, nervous disorders or endocrine-metabolic disorders.
In addition to conditions or disorders caused by magnesium deficiency, magnesium supplements have been shown to have a therapeutic effect in many other conditions or disorders, including, for example, constipation, preeclampsia, leg cramps, cerebral palsy, depression, asthma, cardiovascular diseases, ischemic heart disease, cardiac arrhythmias, hypertension, pregnancy-induced hypertension, strokes, cerebrovascular diseases, osteoporosis, alcohol withdrawal, preterm labor, fatigue, renal stones, kidney, stones, headache, migraine, altitude sickness, premenstrual syndrome, fibromyalgia, muscle weakness, insulin resistance, bronchospasms, hyperlipidemia, mitral valve prolapse, neonatal encephalopathy, and diabetes mellitus.
Magnesium supplementation has been shown to improve myocardial metabolism, to inhibit calcium accumulation and myocardial cell death; to improve vascular tone, peripheral vascular resistance, and afterload and cardiac output, to reduce cardiac arrhythmias and to improve lipid metabolism.
A magnesium deficiency or excess in an organism cannot be quantified as an absolute value, as the magnesium level in the blood is not related with the presence thereof in the deposit sites, as discussed hereinabove. Generally speaking, the means for detecting the magnesium body contents include the detection of blood levels of magnesium, in the patient's plasma or in the serum (whose anomalies generally indicate a disorder in magnesium metabolism and are, normally, the starting point for a set of further specific tests); the detection of magnesium levels in the urine (which gives a measure of the elimination of magnesium via urine, and is normally associated with protein intake, being the Mg/urea ratio in the urine quite constant); the detection of magnesium levels in the spinal fluid; the detection of erythrocytic magnesium (which shows the amount of Mg contained in the bone marrow when erythropoiesis occurs and allows, therefore, an indirect medullary exploration as concerns magnesium); the detection of lymphocytic magnesium; nuclear magnetic resonance with 25Mg (which evidences any modifications in the subcellular distribution of magnesium and in the different chemical-physical structures); and, the detection of magnesium contents in the patient's bones, muscles or any other tissue or organ of interest.
In view of the widespread recognition of the involvement of magnesium in a variety of disorders and conditions, and the increased need in magnesium supplementation, magnesium-containing products became a highly recommended standard of care.
Herein throughout, in the context of magnesium-containing products, magnesium supplements, magnesium formulations and/or magnesium therapy, the term “magnesium” refers to Mg+2 ions, either in a form of free ions in a salt or in a form of a complex.
Currently available Mg-containing products that are aimed at magnesium supplementation are formulated mainly for intravenous or oral administration. An oral route of administration is more convenient, and usually the safest and least expensive, whereas intravenous administration must be performed by a health care worker, and has additionally sparked some concern as to possible elevation of serum levels of magnesium to the toxic range. However, the decreased absorption associated with oral administration poses a significant obstacle in administration (The Merck Manual Home Health Handbook, 2009, Chapter 10).
When administered orally, magnesium was shown to be absorbed primarily in the small intestine in the ileum and jejunum, and the degree of absorption has been shown to depend upon the amount of magnesium already present in the diet and the amount of magnesium administered. As indicated by radioactive 28Mg studies, absorption begins approximately 1 hour after oral intake, plateaus after 2-5 hours, and then declines. After 6 hours Mg absorption is about 80% complete.
Studies have shown that inorganic magnesium salts may have a bioavailability equivalent to organic magnesium salts, depending on the preparation (Firoz and Graber, 2001). It has further been shown that magnesium salts are converted to magnesium chloride in the stomach (Seelig, 1989). Non-absorbed magnesium (not uptaken by cells), due to high oral loads or inefficient absorption, can cause a number of side effects, including diarrhea, heartburn, nausea, and upset stomach.
Currently available magnesium-containing products for oral administration include, for example, magnesium oxide, magnesium carbonate, magnesium hydroxide, magnesium citrate, magnesium lactate, magnesium gluconate, magnesium chloride, magnesium aspartate, magnesium caprilate, magnesium pidulate and magnesium sulfate. Intravenously administered magnesium includes, for example, magnesium sulfate. It is to be noted that oral administration of acidic magnesium salts, which generate relatively strong acids in the stomach (e.g., magnesium chloride and magnesium sulfate) is limited by the tolerable amount that can be taken, since it can cause non-tolerable acidity in the stomach.
In order for Mg-containing product to be therapeutically effective, it should be able to release a form of ionized magnesium which can be uptaken into the cells to perform its essential functions. As noted hereinabove, the level of serum magnesium does not necessarily correlate to levels of cellular magnesium, and therefore the identification of an effective Mg supplementation should be determined by its cellular uptake. Since magnesium has no specific target tissue, its bioavailability cannot be assessed directly. Therefore, other parameters such as retention, absorption, and urinary excretion are used as a measure for magnesium oral bioavailability. Intravenously administered magnesium is considered to be 100% bioavailable.
Several independent studies have been performed in order to evaluate the absorption of different forms of orally administered magnesium supplements. However, conflicting data regarding the absorption rates of magnesium as a function of the supplement formulation are found in the art.
Magnesium oxide capsules were better absorbed than magnesium-L-aspartate HCL tablets as measured by urinary excretion of magnesium, while plasma magnesium levels remained unchanged (Muhlbauer et al., 1991). Magnesium oxide preparation improved serum magnesium in those with low basal serum levels, but not in those with normal/high serum levels, in a study of magnesium absorption in subjects given magnesium-enriched diets followed by either magnesium oxide or magnesium phosphate plus oxide (Altura et al., 1994). The superiority of magnesium oxide absorption over magnesium glycerophosphate was observed in patients with shortened small bowel-induced malabsorption (Ross et al., 2001). Another study showed that MgO was significantly less well absorbed than a comparable amount of Mg citrate as measured by urinary excretion four hours post load (Lindberg et al., 1990). In another study, MgO showed increased urinary excretion as compared with a comparable amount of MgCl2, Mg lactate, and Mg aspartate (Firoz and Graber, 2001). However, in other studies (Schuette et al., 1993 and Schuette et al., 1994) there was no significant difference observed between uptakes of MgO as compared with Mg diglycinate.
Yet another study compared the delivery of MgAc in gelatin capsules to magnesium chloride in enteric-coated capsules. The lower absorption of the enteric-coated capsules was attributed to the 3-5 hour exposure necessary to fully release the capsule's contents, which reduced the small bowel absorptive area to which the Mg is exposed (Fine et al., 1991).
One study on livestock reported that the particle size of the MgO affects its absorption, a phenomenon which could explain the conflicting results about MgO absorption (Xin et al., 1989).
Several means have been devised to overcome the poor absorption of MgO. Efforts were made to utilize small MgO particles, yet, are hindered by the tendency of the magnesium oxide particles to strongly agglomerate. Resulting agglomerates require a high shear force for re-pulverization at the time of incorporation into absorbable preparations, and thus adversely affect other ingredients in any planned preparations.
The present inventor discovered that a special form of magnesium oxide is useful to overcome not only the problems of agglomeration but also provide enhancing bioavailability of magnesium.
Magnesium oxide, also known as the mineral periclase, can be formed by calcination at high temperatures from magnesium carbonate (Liu et al, 1997), by thermal decomposition of magnesium chloride (Jost et al. 1997), or by dehydration of magnesium hydroxide.
The dehydration of magnesium hydroxide (also referred to in the art as brucite), so as to form magnesium oxide and water has been studied extensively in the art (Meyer and Yang, 1962; Barnes and Ernst, 1963; Aranovich and Newton, 1996; L'vov et al., 1998).
It has been shown that this reaction occurs under defined pressure-temperature conditions (see, for example, Schramke et al., 1982; and corresponding Background Art FIG. 1, further discussed hereinbelow).
Schramke et al. (1982) used a method of measuring volume changes of encapsulated samples during the experimentation of the brucite-periclase equilibrium, in order to avoid quenching problems. The results agree with data obtained from thermochemical techniques, as reflected in Background Art FIG. 1. Notably, the curve for the dehydration of brucite and the curve for the hydration of periclase do not demonstrate the same values.
Meyer and Yang (1962) reported that the dehydration curve obtained by temperature quenching and the hydration curve obtained by pressure quenching are about 40° C. apart at elevated pressures. They proposed that the difference between the 2 curves is due to the formation of an intermediate phase, corresponding to a distorted periclase which rapidly rehydrates during quenching.
Barnes and Ernst (1963) investigated the brucite periclase equilibrium at pressures up to 2 kbar using cold-seal hydrothermal pressure vessels with water as the pressure medium. In their study, they developed two procedures to avoid confusing the effects of a back reaction during the quench.
Johnson and Walker (1993) determined accurately the brucite dehydration equilibrium from 1 to 15 GPa. The approach adopted was a combination of differential thermal analysis (DTA) and quenching experiments. The quenching experiments are more reliably interpreted than in other studies because thermal gradients cause diffusive migration of periclase and H2O to different regions of the experimental charge. This separation facilitates quenching of periclase in experiments outside the brucite stability field. In the quenching experiments, samples were brought to the desired pressure and temperature, held there for 30 minutes, and then quenched by shutting off furnace power. Background Art FIG. 2 presents an experimentally determined phase diagram for the dehydration of brucite determined by differential thermal analysis (circles), and quenching techniques (squares), and additionally presenting an interface in which magnesium hydroxide and magnesium oxide were stable (open squares), and temperatures at which both brucite and periclase were stable (half-shaded squares)).
Additional experiments and data from Yamaoka et al., 1970; Irving et al., 1977; Kanzaki, 1991; and Leinenweber et al., 1991, have shown similar results (see, Johnson and Walker, 1993).
Ball and Taylor (1961) have studied the dehydration process of brucite to periclase using X-rays measurements and found that this process involves a formation of spinel-like intermediate, which gave “extra” reflections, and was obtained when a pure brucite crystal was heated in air to 800° C. for 45 minutes. Ball and Taylor have suggested that during the formation of periclase, donor and acceptor regions are developed in the brucite crystal, and that the reaction proceeds not by loss of hydroxyl ions, but rather by gain of cations and loss of protons. The formed cations migrate into the donor regions, and their hydroxyl ions provide all the oxygen for the water that is formed, as shown in Background Art FIG. 3. Ball and Taylor have assumed that the formed spinel-like intermediate has a molecular formula of Mg3O4H2, which corresponds to a molecule of water to which 3 molecules of MgO are complexed to form a kind of hydrate.
Ahdjoudj and Minot (1998) describe ab initio periodic Hartree-Fock calculations of water molecules on MgO and teach that the water molecule does not dissociate on MgO and is adsorbed parallel to the surface, with the main interaction concerning the Mg from the surface and the p-orbital electron pair of the water.
Means for providing magnesium to the human body as a supplement have been proposed in the art. Despite the ability of existing magnesium supplements to increase magnesium levels to some extent, there is a considerable need for an improved magnesium-containing composition, able to enhance the uptake of magnesium in humans. The present invention satisfies these needs due to enhanced bioavailability of a specific hydrate form of magnesium oxide, and provides manifestative health benefits as well.